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Thyroid dysplasia was recognized in WistarHan GALAS rats and confirmed as a heritable congenital disorder. The gene or genes involved were not identified, but homozygous animals with thyroid dysplasia also exhibited stunted growth, had reduced pituitary gland growth hormone (GH) and were hypothyroid. Heterozygous animals exhibited thyroid dysplasia with normal thyroid hormonal homeostasis and no difference in the incidence of preneoplastic or neoplastic lesions in oncogenicity studies.

The uptake of the boron compound Na2B12H10-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial 'Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility' (protocol 11961).The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated.The average boron concentration in the tumor was 19.9 +/- 9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8 +/- 3.3 ppm in the low dose group, the tumor/blood ratios were 0.6 +/- 0.2 and 0.9 +/- 0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2 +/- 0.02 and 0.4 +/- 0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed.BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.

✓ The authors report the underestimated cognitive, mood, and behavioral complications in patients who have undergone bilateral contemporaneous pallidotomy, as seen in their early experience with functional neurosurgery for Parkinson's disease (PD) that is accompanied by severe motor fluctuations before pallidal stimulation.Four patients, not suffering from dementia, with advanced (Hoehn and Yahr Stages III–IV), medically untreatable PD featuring severe “on—off” fluctuations underwent bilateral contemporaneous posteroventral pallidotomy (PVP). All patients were evaluated according to the Core Assessment Program for Intracerebral Transplantations (CAPIT) protocol without positron emission tomography scans but with additional neuropsychological cognitive, mood, and behavior testing.For the first 3 to 6 months postoperatively, all patients showed a mean improvement of motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS), in the best “on” (21%) and worst “off (40%) UPDRS III motor subscale, a mean 30% improvement in the UPDRS II activities of daily living (ADL) subscore, and 60% on the UPDRS IV complications of treatment subscale. Dyskinesia disappeared almost completely, and the mean daily duration of the off time was reduced by an average of 60%. Despite these good results in the CAPIT scores, one patient experienced a partially regressive corticobulbar syndrome with dysphagia, dysarthria, and increased drooling. No emotional lability was found in this patient, but he did demonstrate severe bilateral postoperative pretarsal blepharospasm (apraxia of eyelid opening), which interfered with walking and which required treatment with high-dose subcutaneous injections of botulinum toxin. No patient showed visual field defects or hemiparesis, but postoperative depression, changes in personality, behavior, and executive functions were seen in two individuals. Postoperative abulia was reported by the family of one patient, who lost his preoperative aggressiveness and drive in terms of ADL, speech, business, family life, and hobbies, and became more sleepy and fatigued. One patient reported postoperative mental automatisms, such as compulsive mental counting, and circular thoughts and reasoning during off phases; postoperative depression was found in two patients. However, none of the patients demonstrated these symptoms during intraoperative microelectrode stimulation. These findings are compatible with previous reports on bilateral pallidal lesions. A progressive lowering of UPDRS subscores was seen after 12 months, consistent with the progression of the disease.Bilateral simultaneous pallidotomy may be followed by emotional, behavioral, and cognitive deficits such as depression, obsessive—compulsive disorders, and loss of psychic autoactivation—abulia, as well as disabling corticobulbar dysfunction and apraxia of eyelid opening, in addition to previously described motor and visual field deficits, which make this surgery undesirable even though significant improvement in motor deficits can be achieved.

A case of a 61-year-old diabetic patient who had a new onset simple partial seizure is presented. Past medical history was remarkable for pulmonary sarcoidosis for which the patient was on chronic steroid therapy. Computed tomography scan demonstrated a postcentral abscess which was aspirated under stereotactic guidance. Nocardia asteroides was identified. The patient was placed on intravenous trimethoprim and sulfamethoxazole. He required two further stereotactic aspirations of recrudescences until symptoms resolved. The use of repeated stereotactic aspiration in place of an open surgical procedure is advocated for the treatment of nocardial abscesses.

Functional stereotactic cerebral operations are currently performed with straight electrodes. After physiological exploration, correction of the initial target is frequently necessary and requires multiple penetrations of the brain. This paper describes a robotic three-dimensional electrode probe that can reach targets located within a cylindrical volume from a single approach trajectory. It has been mounted on the neurosurgical robot Minerva, and includes a string electrode, which can protrude out of the side window of a straight cannula and offers a high intrinsic accuracy of 0.25 nun. A simple man-machine interface allows the surgeon to select reference and target points and to activate the probe from a graphics workstation. This paper also analyzes the accuracy of the probe as well as of the whole operating system, food gelatin being used to simulate brain matter.

We describe the development and approach to clinical application of the neurosurgical robot Minerva, including the mechanical structure of the robot and the software developed to perform intracranial neurosurgical operations with accuracy, smoothness, and safety. The first eight operations have been undertaken on patients requiring stereotactic brain biopsy. We describe the ongoing developments, including improved sterilization features, force sensors, nonlinear electrostimulation probe, and implantation of living encapsulated cells, all of which have entered a test phase. The goals are increased safety and capability to perform simple three-dimensional operations. This research should ease the way for new complex operations that are difficult to perform manually today.

Disseminated intravascular coagulation (DIC) is an extremely rare complication during elective brain tumor surgery. We report the case of a life-threatening intraoperative hemorrhagic diathesis due to a fulminating DIC during the removal of a grade III parietooccipital astrocytoma in a patient with a history of three pulmonary embolisms. Intraoperatively, the patient required 13 U of blood, 9 U of fresh-frozen plasma, and 5.45 L of colloids and crystalloids (total volume infused during the procedure: 12.5 L). Bleeding persisted for 24 h and required further blood component therapy. Laboratory data support the diagnosis of DIC: decreased fibrinogen and platelet count, prolonged thrombin and prothrombin times, and the presence of fibrin monomers. With aggressive and swift treatment of the DIC, the patient survived with transient neurological worsening.

At the 1989 meeting of the World Society for Stereotactic and Functional Neurosurgery in Maebashi, the authors presented the concept and design of a stereotactic neurosurgical robot. The first prototype has now been completed and has entered clinical testing. The characteristics are as follows. The robot is positioned behind the CT scan and operates inside the CT gantry. It is linked to the CT table and moves freely along its longitudinal axis, allowing for intraoperative scanning at any cranial level. The patient''s body rests on the CT table, but the stereotactic headframe is fixed to the robot, allowing precise measurements of the head position under stereotactic conditions. During scanning, each CT slice appears immediately on the robotic workstation for selection of target and trajectory. In addition to the tool for automatic penetration of the skin, skull, and meninges, the robot is able to handle two other stereotactic instruments and to perform a complete stereotactic procedure without physical intervention by the physician. So far, depth electrodes and biopsy instruments have been developed for use by the robot. Since all parts of the robot were designed solely for stereotactic neurosurgery, integration of safety aspects was optimized. The first operations using an aspiration biopsy probe were successfully performed on 2 patients with malignant intracerebral cystic lesions on September 4, 1993.

The anatomy of the lateral aspect of the lumbar spine and our lateral microsurgical technique for extreme lateral lumbar disc herniations (ELLDH) is described. This study was based on the microdissection of 4 cadavers, on the morphometric evaluation of these as well as 6 dried cadaver spines and 8 lumbar CT scans, and on the use of this technique on over 200 cases. Level dependent changes in the posterior arch cause a shift of the disc space distally relative to the facet joint, an increasing amount of bone to overlie the intervertebral foramen, and a decreasing amount of working space within the exposure in the caudal direction. Therefore, more bone removal from the lateral aspect of the pars interarticularis and supero-lateral aspect of the facet joint is required in the lower lumbar spine. When the exposed ligamentum flavum is resected, the dorsal root ganglion is seen and access to the herniation and disc space is achieved. Level dependent changes in the pedicles and transverse processes lead to an alteration in the course and relationships of the nerves, thereby influencing the pathophysiology of and surgical technique for the ELLDH. The operative target is the lateral aspect of the pars interarticularis and not the intertransverse space as has been previously described. Our techniques allows for the early identification of the nerve with minimal risks of injury to it, to the adjacent vessels and to the structural integrity of the facet joint and pars interarticularis.

Six cases of cyst of the ligamentum flavum with compression of a lumbar nerve root are reported. All patients exhibited recurrent back pain and sciatica. Investigation included computed tomography, myelography, or both. The correct diagnosis was reached before operation in only half the patients. High-resolution computed tomography performed in the four last patients outlined the cystic lesion with its low-density center. Surgical excision was performed in all patients. Microscopic examination showed a dense fibrous cyst arising from the ligamentum flavum. The lumen contained myxoid or necrotic material, but no epithelial lining. Cysts of the ligamentum flavum must be considered in the differential diagnosis of causes of sciatica. A firm radiological diagnosis may, at present, still require myelography combined with high-resolution computed tomography. Differentiation from synovial or ganglion cysts of the spine is discussed.

The first part of this work, published in 1988, included 25 patients who had computed tomographic (CT) scans without contrast enhancement and plain x-rays of the lumbar spine before, 1 week after, and 6 to 7 weeks after a successful operation for lumbar disc herniation. The present study extends the follow-up period to 3 years in 19 of the 25 original patients. Clinical examinations, lateral plain x-rays, and CT scans without contrast enhancement of the operated disc were repeated. The results indicate a decrease or even a disappearance of the hyperdense extradural material thought to represent fibrosis. An image suggestive of persistent disc herniation was still present in 5 of 8 patients with this finding on early postoperative CT scans. Persistent intradiscal gas was seen in nearly half of the patients. Total normalization of the posterior extraspinal structures was the rule. There was no correlation between CT appearance and residual complaints of the patients. CT scans without contrast enhancement may be sufficient to guide the surgeon in postoperative patients with massive signs and symptoms of recurrent root compression in whom a second operation is indicated on clinical grounds. In all other cases, myelography followed by CT scans is considered appropriate to investigate failed back surgery syndrome. (Neurosurgery 29:1-7, 1991)

The first European clinical trial on BNCT (EORTC protocol 11961) started in 1997.1 Thjs is a phase I study, aimed to define the Maximum Tolerated Dose and Dose Limiting Toxicity in gliobastoma patients using BSH as boron carrier and fractionated radiation at the Epithermal Neutron Facility at Petten. Beside the evaluation of the systemic toxicity of BSH, and the early radiation toxicity in the irradiated volume, special emphasis has been placed on the late radiation morbidity. In addition survival will be observed. Up to this date 14 patients have been entered into the study, 12 males and 2 females at six Neurosurgery Centers in five European countries.

In October 1997, after a preparatory phase of 8 years, the first patient in Europe was treated by BNCT at the High Flux Reactor (HFR) of the European Commission in Petten, The Netherlands.1 The preparation for the first clinical BNCT trial in Europe included comprehensive scientific experimental and human investigations with the boron compound borocaptate sodium (BSH).2,3 A multitude of open legal and administrative questions had to be overcome. Furthermore a complex structure had to be organized and the procedures had to be defined how to perform a multi-national, multi-institutional study using a nuclear reactor distant from hospital for patient treatment performed by an international team on a multidisciplinary base.4 The international standards of clinical research as well as the accepted rules and definitions of conventional radiotherapy were applied, involving independent experts in order to assure the quality of the study and the quality of the Performance of patient treatment. The goal was to execute the project to a very high Standard as would be expected in the leading radiotherapy depart-ments in Europe.5

Endoscopic percutaneous ventriculostomy (EPV) is a new technique to restore the flow of the cerebrospinal fluid (CSF) to the basal cistern in patients with non-communicating hydrocephalus (NCH). Cardiac gated MRI techniques have been applied to demonstrate normal and abnormal CSF flow in humans. The aim of this study was to evaluate the ability of a new multislice spin echo dynamic MRI technique and amplitude and phase reconstruction to demonstrate the impairment of CSF flow through the aqueduct preoperatively and to assess the patency of the ventriculostomy after surgery. Thirteen patients with NCH were studied with dynamic MRI before and after EPV using multiple sagittal multislice gated SE acquisitions to demonstrate the CSF flow. Nine patients were clinically improved by EPS, two remained unchanged and two deteriorated. The permeability of the ventriculostomy was confirmed in all patients. We think that MRI flow studies are useful to demonstrate the site of impairment of CSF flow and its aetiology preoperatively, and to assess the permeability of the ventriculostomy after surgery in a non invasive way.

Object. The aim of this study was to evaluate the long-term safety and efficacy of bilateral contemporaneous deep brain stimulation (DBS) in patients who have levodopa-responsive parkinsonism with untreatable motor fluctuations. Bilateral pallidotomy carries a high risk of corticobulbar and cognitive dysfunction. Deep brain stimulation offers new alternatives with major advantages such as reversibility of effects, minimal permanent lesions, and adaptability to individual needs, changes in medication, side effects, and evolution of the disease. Methods. Patients in whom levodopa-responsive parkinsonism with untreatable severe motor fluctuations has been clinically diagnosed underwent bilateral pallidal magnetic resonance image—guided electrode implantation while receiving a local anesthetic. Pre- and postoperative evaluations at 3-month intervals included Unified Parkinson's Disease Rating Scale (UPDRS) scoring, Hoehn and Yahr staging, 24-hour self-assessments, and neuropsychological examinations. Six patients with a mean age of 55 years (mean 42–67 years), a mean duration of disease of 15.5 years (range 12–21 years), a mean “on/off” Hoehn and Yahr stage score of 3/4.2 (range 3–5), and a mean “off” time of 40% (range 20–50%) underwent bilateral contemporaneous pallidal DBS, with a minimum follow-up period lasting 24 months (range 24–30 months). The mean dose of levodopa in these patients could not be changed significantly after the procedure and pergolide was added after 12 months in five patients because of recurring fluctuations despite adjustments in stimulation parameters. All but two patients had no fluctuations until 9 months. Two of the patients reported barely perceptible fluctuations at 12 months and two at 15 months; however, two patients remain without fluctuations at 2 years. The mean improvements in the UPDRS motor score in the off time and the activities of daily living (ADL) score were more than 50%; the mean off time decreased from 40 to 10%, and the mean dyskinesia and complication of treatment scores were reduced to one-third until pergolide was introduced at 12 months. No significant improvement in “on” scores was observed. A slight worsening after 1 year was observed and three patients developed levodopa- and stimulation-resistant gait ignition failure and minimal fluctuations at 1 year. Side effects, which were controlled by modulation of stimulation, included dysarthria, dystonia, and confusion. Conclusions. Bilateral pallidal DBS is safe and efficient in patients who have levodopa-responsive parkinsonism with severe fluctuations. Major improvements in motor score, ADL score, and off time persisted beyond 2 years after the operation, but signs of decreased efficacy started to be seen after 12 months.

Background and purpose : This work was undertaken to improve the definition of target volumes for radiosurgery using the angiographic and CT data. Materials and methods : The basis of this new method is to combine both imaging modalities and to compare them in each representation, i.e. to plot the volume obtained by angiography on CT images and also the contours defined by the CT on angiographic films. To obtain the angiographic volume, the radiographs are taken at several incidence angles. The X-ray sources position and the position of the films are determined using rectangular markers, then the intersection of all the loci of the target volume are calculated. Results : Verifications with a phantom show the accuracy of the procedure and the benefit obtained by increasing the number of angles of incidence in the angiographic imaging. The centre of gravity of the experimental target could be localized to an accuracy of better than 0.4 mm. The method was used in 11 clinical cases with excellent clinical results. Conclusions : The method can be easily applied and improves the delineation of target volumes in radiosurgery. CT data counterbalances the relative weakness of angiography concerning the three-dimensional geometry. Angiography adds useful information on the blood flow that is not shown in CT. Almost all the presented clinical cases benefit from the technique described here.

Study design This prospective study examines the appropriateness of indications for surgery of herniated intervertebral disc and spinal stenosis in patients undergoing surgery in a university hospital setting. Objective To evaluate the appropriateness of surgery using explicit criteria developed by an expert panel in the United States. Summary of background data The use of surgery for herniated intervertebral disc and spinal stenosis varies widely within and among countries. It has been postulated that the main reason for treatment failure is poor selection of candidates for the procedure. Methods The authors prospectively evaluated appropriateness of surgical indications for herniated lumbar intervertebral disc or spinal stenosis in 328 consecutive patients undergoing the operation in two university neurosurgery departments. Outcome was measured 1 year after surgery by a standardized interview. Results Indications for surgery were considered to be appropriate or equivocal in 202 (62%) patients and inappropriate in 126 (38%). Among the 126 inappropriate procedures, 66 were so rated because of insufficient activity restriction before the procedure. One year after surgery, 74% of the patients perceived the results of the operation as good or very good. Conclusions Appropriateness as measured by the criteria established by the American panel identified a large percentage of day-to-day practice in the two surgical units as inappropriate. However, use of criteria that include new findings about lack of efficacy of bed rest probably would lower this percentage. Criteria of appropriateness of medical and surgical procedures, developed through the panel process, need to be updated regularly.

The disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

The biodistribution of boron sulfhydryl (BSH) was evaluated for boron neutron capture therapy of brain tumors. A selective boron delivery to the neoplasm is a prerequisite for successful therapy. The uptake of BSH after intravenous administration was analyzed in neoplastic and normal tissues in 61 patients undergoing craniotomies for intracranial tumors. The patients received 10 to 100 mg of BSH/kg (5-50 mg of 10B/kg) body weight, 2 to 72 hours before surgery. The tumor boron concentrations ranged from 0.2 ppm (micrograms/g) in a low-grade glioma to 19.5 ppm in a high-grade glioma. The tumor to blood boron ratio rose above 1 in 15 of 24 high-grade intracerebral tumors, 18 h or more after BSH infusion. The boron concentration in high-grade tumors was heterogeneous. Low-grade intracerebral tumors showed a low boron concentration with a tumor to blood ratio below 1. Extracerebral tumors, mainly meningiomas, showed boron concentrations comparable with high-grade tumors, with a tumor to blood ratio above 1 in 10 of 17 patients. The boron concentrations in skin and muscle compared roughly with the blood values. Boron did not enter normal brain in any significant amount. In high-grade tumors, tumor to brain ratios were above 2. Low boron concentrations in normal brain make BSH safe for a Phase I normal tissue tolerance study. Computed tomographic contrast enhancement was evaluated to tumor boron uptake for 30 patients. Tumor enhancement on computed tomography does not permit the prediction of individual tumor boron concentrations; however, the absence of a contrast enhancement was always associated with low boron uptake.

A retrospective analysis of clinical characteristics of 178 consecutive patients with extreme lateral lumbar disk herniation, amongst 3047 patients operated on for herniated lumbar disc, is presented. The level specific incidence of extreme lateral disc herniation (ELLDH) ranged from a low of 4.5% at L4-5 to peak of 17.4% at L3-4 although the largest number of ELLDH occurred at L4-5 and L5-S1 for a total number of 139 cases (78.1%). 43.6% of all L3 radiculopathies were caused by an L3-4 ELLDH, whereas only 4.4% of all L5 radiculopathies were caused by an L5-S1 ELLDH. Leg pain, either of the sciatic or the femoral type, was the first and dominant clinical symptom of radiculopathy, but pain radiation occurred not always in the appropriate dermatomal segment. ELLDH at upper levels (L2-3 and L3-4) caused usually none or only minor low back signs (76.2%), whereas ELLDH at lower levels more often caused moderate or major lumbar symptoms and signs (59.6%). Positive femoral nerve traction test with upper ELLDH showed a high frequency (84.4%) and reliability and is therefore an important clinical parameter in this situation. Motor deficits occurred more often (78.8%) than sensory deficits (46.6%), were usually of the monoradicular type and were therefore a more reliable clinical sign than sensory disturbances.

The use of borocaptate sodium (BSH) for Boron Neutron Capture Therapy (BNCT) has been studied since 1968. BSH has shown differential accumulation in rodent tumor models both subcutaneously and intracerebrally implanted. BSH administration to humans for BNCT has also been reported [1,2,3,4], including at this symposium [see report by D. Haritz]. In 1990, we presented the biodistribution of BSH in 28 patients with various intracranial tumors [5]. This compound showed accumulation in most high grade intracerebral tumors and low grade extracerbral tumors with a variable kinetic; a delay of at least 12 hours after administration was usually necessary to obtain a positive tumor to blood ratio. In order to obtain more substantial information on the distribution pattern, and to determine an adequate dose to be given before neutron radiation, we have extended this investigation to a larger number of patients.

Boron Neutron Capture Therapy (BNCT) can only be conceived in the framework of a large multidisciplinary team. Clinical papers presented at the Fifth International Symposium on Neutron Capture Therapy for Cancer can roughly be divided into 3 groups, according to the team to which the authors belong, each of which has its particular concerns, reflecting the level of advancement of the project. A number of papers stemmed from authors which were already applying BNCT to patients with intracranial tumors and melanomas,1-8 and these mostly reflected attempts to refine and improve the current treatment methods. An equal number stemmed from authors who intended to start clinical trials shortly,9-18 dealing with beam and treatment room design, quality control and clinical biodistribution of boron compounds, and protocol design. A small number of clinical papers dealt with those lesions, which may become candidates for BNCT, as well as with new boron compounds, preparing the future beyond intracranial tumors and melanomas, and beyond BSH and BPA.3,19,20

The research program of the European Concerted Action on Boron Neutron Capture Therapy (BNCT) for Tumors is now approaching a clinical trial with epithermal neutrons and borocaptate sodium (BSH) for 10B delivery. The therapeutic beam prepared with a liquid argon filter has become available for normal tissue tolerance studies in healthy dogs injected with BSH early in 1992. It is therefore timely to draft a protocol for the initial patient trial.

Current methods for quantitative determination of boron in biological tissues include Inducticely Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) and Quantitative Neutron Capture Radiography (QNCR). These sophisticated techniques measure independent physical properties. Precise values of B-10 concentrations are reported in literature, even in the subppm range. Nevertheless, convincing data on calibration curves and quality control are lacking. Furthermore, there are no reports on direct comparison of ICP-AES and QNCR. In order to obtain reliable data, we analyzed our specimens - whenever available - by both methods.

In a previous communication we have reported the results of a biodistribution study of intravenous borocaptate sodium (BSH) administered to 28 patients undergoing craniotomy for various intracranial tumors10. The measured boron concentrations in tumor, blood, and normal cranial tissues led to the tentative conclusion 1) that BSH readily enters most malignant intracerebral tumors, 2) that some retention of the drug occurs in these tumor, leading to an improvement of the tumor-to-blood ratio over the first 18 hours, and possibly later, and 3) that BSH is virtually excluded from normal brain.

The authors present a simple software written in Turbo Pascal which allows placement of multiple parallel sources for interstitial brachytherapy using the Brown-Roberts-Wells CT stereotactic system. The user can choose any direction in space, independently from the CT plane, and any number of linear sources arranged on one or more hypothetical cylinders of variable radius. The sources can be rotated on the cylinder in order to avoid critical structures. This small program runs on any IBM compatible computer.

The therapeutic as well as the undesired effects of Boron Neutron Capture Therapy (BNCT) largely depends upon the absolute and relative 10B concentrations in tumors and in normal tissues and body fluids. Our present work on BSH in patients with intracranial neoplasms has been prompted by crucial questions regarding: tumor levels, tumor-to-normal tissue ratios, variations between different tumors, variations inside the same tumor, correlation between histology and 10B levels, time course of BSH uptake, pharmacokinetics of BSH, Temptative answers to some of these questions have been worked out for animals and experimental animal tumor models. For humans, Hatanaka et al. [2] have published boron concentrations measured at the time of re-operation and actual BNCT in 60 patients. Eleven to 17 hrs after intra-arterial or intravenous administration of 40 to 80 mg of 10B/kg as BSH, 26 glioblastoma patients yielded a median 10B concentration in the tumor of approximately 15 ppm and a median tumor-to-blood ratio of 1.1. In 13 cases of anaplastic astrocytomas the values were comparable with a median tumor concentration of approximately 22 ppm and a tumor-to-blood ratio of 1.4. In 4 cases of astrocytomas grade I-II, the median concentration dropped to around 5 ppm and the tumor-to-blood ratio remained always below 0.6. Beside Hatanaka’s findings, the literature contains only anecdotal data on the situation in humans [1,4,5].

Treatment beam and irradiation room of the High Flux reactor in Petten are close to completion and pre-clinical dog irradiation studies were started in summer 1991. It is therefore timely to draft the preliminary protocol which will be applied to the initial patient study using borocaptate sodium (BSH) and epithermal neutrons for the treatment of malignant gliomas. At this stage emphasis is put on inclusion criteria, follow-up, and data collection, rather than on details of BNCT itself. The latter are to be finalized once the results of the irradiation at the treatment position of normal dogs with and without intravenously administered BSH are available.

Brain gliomas have been surgically removed for over 100 years. In the early days mortality was over 20%, but it was obvious even then that extensive resection produces better results than does minimal resection, with a mortality of 10%. The mortality was reduced dramatically, to below 3%, with the introduction of dexamethasone in the early 1960s (Jelsma and Bucy 1967). Patients were also seen to be in better neurological condition in the immediate postoperative period after an extensive resection than after a partial resection, and they had a longer mean survival. More recent studies have shown that surgery alone prolongs survival by about 14 weeks (Shapiro 1982; Walker et al. 1978). Postoperative morbidity is under 20% and is not affected by the extent of surgical resection (Fadul et al. 1988). On the contrary, patients with complete resection suffer fewer complications such as hemorrhage or herniation than those with partial resection or biopsy only. However, total resection of a tumor situated in the midline or in the parietal lobes may leave the patient with severe neurological deficits.

The robot technology was introduced into a new stereotactic neurosurgery system for applications to biopsy, blind surgery, and functional neurosurgery. The authors have developed a newly designed prototype microsurgical robot, designed to allow a biopsy needle to reach the target such as a cerebral tumor within a brain automatically on the basis of the X, Y, and Z coordinates obtained by CT scanner. This robot is so small that it can be driven in a CT scanner gantry. It consists mainly of the link mechanism and the insertion mechanism. We constructed the link mechanism and investigated its working space.

The design of a robot for functional stereotactic surgery which is under construction in our laboratory is described. The main features include operation inside the computed tomographic (CT) scanner, the possibility of intraoperative CT scanning and complete handling of the stereotactic probes by the robot.

Twenty-five patients with good outcome after operation for lumbar disc herniation underwent unenhanced computed tomography (CT) and plain radiography of the lumbar spine before, 5 to 7 days after, and 6 lo 7 weeks after the operation to define the radiological features ofthe postoperative disc and spinal canal. After operation, the center of the disc appears hypodense. The anterior and lateral borders remain sharply delimited, but in 44% of the cases the posterior border shows an image suggesting the persistence of disc herniation. In 84% of the cases, there are major changes in the spinal canal with complete occlusion of the extradural space on the operated side by a heterogeneous material the attenuation value of which ranged between those of cerebrospinal fluid and disc. The outline of the dural sac and of the nerve root is lost. This aspect did not significantly change between the 1st and the 6 th postoperative week, except for the disappearance of any air within the canal and a slight movement on the dural sac toward the operated side. From these major radiological modifications found in asymptomatic postoperative patients, it is concluded that positive CT in patients with the failed back surgery syndrome has limited value. Myelography is preferred as the primary neuroradiological investigation.

Extreme lateral lumbar disc herniation (ELLDH) occurring into and/or outside the intervertebral foramen was encountered in 95 cases amongst 1600 operations for herniated lumbar disc (6%): 43% occurred at L5-S1, 38% at L4-5, 18% at L3-4, and 1% at L2-3. The incidence amongst all herniations at one particular level was 6% at L5-S1, 4% at L4-5, and 18% at L3-4. The clinical presentation varied according to the level of extreme lateral disc herniation, but was not different from the presentation of a classical paramedian herniation occurring one level above. Forty-three patients were investigated with computed tomography (CT) only, 2 with myelography only, and 50 with both. CT always clearly demonstrated the pathology, but some cases are presented to illustrate the differential diagnosis. Myelography was normal in 13 cases; in 27 cases it showed a typical shortening and enlargement of the nerve root sheath which enters the affected intervertebral foramen. At operation, a total facetectomy was performed in 52 patients, a partial facetectomy in 34, and a lateral approach to the intervertebral foramen in 9. The lateral approaches, either paramuscular with retraction of the paraspinal muscles from the midline, or transmuscular by splitting of the paraspinal muscles, are described and illustrated in detail.

Extracts of Chlorella pyrenoidosa, Euglena gracilis var. bacillaris, spinach, barley, Dictyostelium discoideum and Escherichia coli form an unknown compound enzymically from adenosine 5′-phosphosulphate in the presence of ammonia. This unknown compound shares the following properties with adenosine 5′-phosphoramidate: molar proportions of constituent parts (1 adenine:1 ribose:1 phosphate:1 ammonia released at low pH), co-electrophoresis in all buffers tested including borate, formation of AMP at low pH through release of ammonia, mass and i.r. spectra and conversion into 5′-AMP by phosphodiesterase. This unknown compound therefore appears to be identical with adenosine 5′-phosphoramidate. The enzyme that catalyses the formation of adenosine 5′-phosphoramidate from ammonia and adenosine 5′-phosphosulphate was purified 1800-fold (to homogeneity) from Chlorella by using (NH4)2SO4 precipitation and DEAE-cellulose, Sephadex and Reactive Blue 2–agarose chromatography. The purified enzyme shows one band of protein, coincident with activity, at a position corresponding to 60000–65000 molecular weight, on polyacrylamide-gel electrophoresis, and yields three subunits on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis of 26000, 21000 and 17000 molecular weight, consistent with a molecular weight of 64000 for the native enzyme. Isoelectrofocusing yields one band of pI4.2. The pH optimum of the enzyme-catalysed reaction is 8.8. ATP, ADP or adenosine 3′-phosphate 5′-phosphosulphate will not replace adenosine 5′-phosphosulphate, and the apparent Km for the last-mentioned compound is 0.82mm. The apparent Km for ammonia (assuming NH3 to be the active species) is about 10mm. A large variety of primary, secondary and tertiary amines or amides will not replace ammonia. One mol.prop. of adenosine 5′-phosphosulphate reacts with 1 mol.prop. of ammonia to yield 1 mol.prop. each of adenosine 5′-phosphoramidate and sulphate; no AMP is found. The highly purified enzyme does not catalyse any of the known reactions of adenosine 5′-phosphosulphate, including those catalysed by ATP sulphurylase, adenosine 5′-phosphosulphate kinase, adenosine 5′-phosphosulphate sulphotransferase or ADP sulphurylase. Adenosine 5′-phosphoramidate is found in old samples of the ammonium salt of adenosine 5′-phosphosulphate and can be formed non-enzymically if adenosine 5′-phosphosulphate and ammonia are boiled. In the non-enzymic reaction both adenosine 5′-phosphoramidate and AMP are formed. Thus the enzyme forms adenosine 5′-phosphoramidate by selectively speeding up an already favoured reaction.

O-Methylthreonine (OMT) inhibits the growth of plated Rosa cells (ID50≃6·10(-6)M). Isoleucine is able to reverse efficiently and specifically this OMT toxicity. From OMT-resistant colonies occurring at a frequency of 1.58·10(-7) variants per cell plated at 10(-4)M OMT, the variant strains OMT(R)-1 and OMT(R)-2 were isolated, cloned via protoplasts and characterized. Both variants were ten times more resistant to OMT than the wildtype and were cross-resistant to another isoleucine analog, DL-4-thiaisoleucine. The resistant variants retained their resistance after storage for three years in liquid nitrogen. Both resistant strains were stable for several months when subcultured in the absence of OMT although it was shown in a reconstitution experiment that wildtype cells overgrow OMT(R)-2 variant cells if co-cultivated for many passages in drug-free medium. One case of instability was observed upon long-term subculturing in drug-free medium: the strain OMT(R)-1D(*) partially lost phenotypic properties. Resistance to OMT was followed qualitatively by a new method based on inhibition-zone formation in cell suspensions plated in agar medium. The OMT-resistant variants showed a reduction in sensitivity of the enzyme L-threonine deaminase to feedback inhibition by isoleucine, a decreased stability of L-threonine deaminase when stored at-18°C or incubated at +55°C and a two- to threefold increase of the free isoleucine pool within the cells. The genetical events and the biochemical mechanisms which might lead to the observed stable and biochemically defined character are discussed with particular reference to the high ploidy level of the Rosa cell line.

Roots of spinach (Spinacia oleracea L.) seedlings contained only a very low activity of adenosine 5′-phosphosulfate sulfotransferase compared to the cotyledons. Adenosine 5′-phosphosulfate sulfotransferase activity increased about tenfold in cotyledons during greening. Preparation of organelle fractions from spinach leaves by a combination of differential and isopycnic density gradient centrifugation showed that adenosine 5′-phosphosulfate sulfotransferase banded with NADP-glyceraldehyde-3-phosphate dehydrogenase, a marker enzyme for intact chloroplasts. In the fractions of peroxisomes, mitochondria and broken chloroplasts virtually no adenosine 5′-phosphosulfate sulfotransferase activity was measured. Comparison with the chloroplast enzyme NADP-glyceraldehyde-3-phosphate dehydrogenase indicates that in spinach, adenosine 5′-phosphosulfate sulfotransferase is localized almost exclusively in the chloroplasts.

Two cases of extradural haematoma of delayed onset, demonstrated by serial computed tomography (CT), are presented. the first patient developed a fatal posterior fossa haematoma, which was not present on the initial CT four hours after the accident. The second patient developed a right parietal haematoma, which was not present on the CT two and a half hours after the accident. These cases are in disagreement with the hypothesis that extradural haematomas reach near maximum size within minutes after trauma.

Four nitrate non-utilizing clones of Hyoscyamus muticus, obtained by a total isolation method, possess all the known characteristics of cnx-type nitrate-reductase-deficient variants: 1) strict dependence on a reduced nitrogen source such as a mixture of amino acids; 2) chlorate resistance; 3) normal nitrate uptake; 4) lack of nitrate-reductase and xanthine-dehydrogenase activities, but presence of cytochrome-c-reductase and nitrite-reductase activities; 5) in vitro nitrate-reductase complementation with a molybdenum cofactor source. Two of the clones (MA-2 and I2D12) are molybdate repairable in vivo, whilst the other two clones (VIC2 and XIVE9) are not.

The effects of three different pretreatment techniques on ICP and MAP responses to pin head-holder application (HH) were studied. Thirty-two patients for elective intracranial surgery were assigned randomly to three pre-treatment groups: group I-local scalp infiltration with lidocaine (6-8 ml of 2% solution); group II-deepening of general anesthesia with either thiopentone (2 mg/kg) or propofol (0.6 mg/kg); and group III-intravenous fentanyl (4 mug/kg). Two anesthetic techniques were used, subdividing the three groups into subgroup A (thiopentone-isoflurane) and subgroup B (propofol). Measurements of MAP, cerebrospinal fluid pressure (CSFP), cerebral perfusion pressure (CPP), and heart rate (HR) were made at pretreatment, just before HH (time T0: baseline), and 0.5, 1, 2, 3, 4, and 5 min after HH. Within each group, MAP, HR, CPP, and CSFP varied similarly in both subgroups, so the data from A and B were cumulated. After HH application, MAP, HR, CPP, and CSFP increased in all groups, but significantly less in group I. The maximal MAP increase occurred at T1 and was 6.7 +/- 2.2% in group I, 27.9 +/- 4.9% in group II, and 27.1 +/- 6.5% in group III (difference between I and II-III: p

✓ Posterior inferior cerebellar arteries originating from the vertebral arteries between the axis and the atlas were demonstrated angiographically in a 12-year-old boy. The patient presented with tetraparesis of sudden onset after a gymnastic exercise. There was no recognizable trauma.

Publisher Summary This chapter describes the assay, purification, and properties of this enzyme from Chlorella pyrenoidosa. The reaction of APS and ammonia to form APA catalyzed by adenylylsulfate-ammonia adenylyltransferase is widely distributed among various groups of organisms. Two methods are used to measure enzyme activity. When both the adenylyltransferase and APS-sulfohydrolase are present in the enzyme preparation, an assay based on the conversion of [U- 14 C]APS to [ 14 C]APA or 5'-[ 14 C]AMP is used. When highly purified enzymes are assayed, sulfate release from [ 35 S] APS is measured. Ammonia is added when the transferase or transferase plus sulfohydrolase activity is to be measured; ammonia is omitted when only the sulfohydrolase activity is assayed. PSS]APS is prepared from adenosine 3'-phosphate 5'-phospho[ 35 S] -sulfate ([ 35 S]PAPS) by treatment with 3'-nucleotidase as described previously, except that the final product is passed through 2 ml of Dowex 50W-X8 (100-200 mesh) cation-exchange resin in the sodium form in a Pasteur pipette to convert the products to the sodium salts. The adenylylsulfate-ammonia adenylyltransferase activity has also been shown to be present in ammonium sulfate fractions obtained from crude extracts of Euglena, spinach, barley, Dictyostelium diseoideum, and Escherichia coli .

A variant clone of Hyoscyamus muticus (VIIIB9) with a specific, stable requirement for tryptophan has been shown to have the following characteristics: (i) no accumulation of tryptophan from anthranilic acid; (ii) growth on added tryptophan or indole but not on anthranilic acid; (iii) accumulation of indole-3-glycerol phosphate and other indole derivatives; (iv) extractable activity of the enzymes for tryptophan biosynthesis, including the partial reaction 2 of tryptophan synthase but not reactions 1 or 3. Thus these data provide in-vivo evidence for the existence of a two-component, bacterial-type tryptophan synthase in plants, the tryptophan auxotrophy of VIIIB9 probably being the consequence of a mutation in the α-subunit of the tryptophan-synthase complex.

We have extracted and purified a nucleotide from cells of Chlorella , pyrenoidose Chick which shares the following properties with adenosine 5′ phosphoramidate; electrophoretic mobility in sodium bicarbonate and in sodium borate buffer (pH 8.0); retention time on high performance liquid chromatography; ultraviolet absorption spectrum at pH 1–2 and 7–9; a yield of one mole each of adenine, ribose, total phosphate and ammonia released at low pH; and formation of adenosine 5′ monophosphate on acidification or treatment with 3′:5′-cyclic-nucleotide phosphodiesterase (EC3.1.4.17). Although formation of APA from its precursor adenosine 5′ phosphosulfate during extraction and purification is not expected this appears to be excluded by the use of low temperature throughout purification and the finding that [ 14 C] APS added before extraction does not significantly label the adenosine 5′ phosphoramidate isolated. Thus adenosine 5′ phosphoramidate appears to be a normal constituent of Chlorella cells like the enzyme which forms it: adenylyl sulfate: ammonia adenylyl transferase.

A combination of differential centrifugation and isopycnic sucrose density gradient centrifugation of extracts from spinach leaves (Spinacia oleracea L.) shows that about 20% of the O-Acetylserine sulfhydrylase are associated with chloroplasts. No appreciable amounts of O-Acetylserine sulfhydrylase band with mitochondrial and peroxisomal marker enzymes.

There was no disturbance in the growth of Lemna minor L. with a SO2 concentration of up to 0.3 ppm in air. A SO2 concentration of 0.6 ppm caused an initial depression of the growth rate of about 25%, but in the course of adaptation, the rate rose to the values of the control. The average dry weight per frond was not influenced by the SO2 fumigation. The initial sporadic appearance of chloroses by fumigation with 0.6 ppm SO2 was considered a sign of the proximate toxicity limit for Lemna minor L. With 0.15 ppm SO2 in air, the size of the fronds was reduced. The average surface of the fronds was diminished by 0.3 ppm SO2 for about 16% as compared with the control plants. The protein remained quantitatively uneffected up to a SO2 concentration of 0.6 ppm. As a qualitative influence of SO2, the nitrogen content of the proteins remained constant, but the sulfur content of the proteins increased. Under 0.3 and 0.6 ppm SO2, the starch content decreased immediately by 20–30%, under 0.15 ppm SO2 the decrease reached the same level after a longer time than in the case of the higher concentrations.

The case of an adult patient with a small frontoparietal convexity meningioma surrounded by a huge cyst is reported. The cyst fluid had a very high protein content, but there was no distinct cyst wall. Knowledge of the radiological features of this rare condition may prevent confusion with a malignant tumour.